Cyclopeptide derivatives

ABSTRACT

The invention relates to compounds of the formula (I) R1 Q1 XQ2 R2, in which: Q1, Q2, each independent of one another, are missing or are NH(CH2)n CO; R1, R2, each independent of one another, are missing or are cyclo(ArgGlyAspZ), wherein Z is missing in the side chain of Q1 or Q2 or if Q1 and/or Q2 are missing, is bound to X, at least one of the groups R1 or R2 always having to be included; X is COR 18 CO, and if R1 Q1 or R2 Q2 are missing is R10, R13, R16, HetCO or a fluorescent pigment residue linked through a CONH, COO, NHC (═S)NH, NHC(═O)NH, SO2 NH or NHCO bond; and Z, R10, R13, R16, R18, Het and n have the meanings given in claim  1.  The invention also relates to the salts of said compounds. Said compounds and their salts can be used as integrin inhibitors, in particular for the prevention and treatment of circulatory diseases, thrombosis, heart infarct, coronary heart diseases, arteriosclerosis, angiogenic diseases and in tumor therapy.

[0001] The invention relates to compounds of the formula I

R¹—Q¹—X—Q²—R²   I

[0002] in which

[0003] Q¹, Q² are, in each case independently of each other, eitherabsent or —NH—(CH₂)_(n—CO—,)

[0004] R¹, R² are, in each case independently of each other, eitherabsent or cyclo-(Arg-Gly-Asp-Z), where Z is bonded in the side chain toQ¹ or Q² or, if Q¹ and/or Q² is/are absent, to X, and

[0005] where at least one of the radicals R¹ or R² must always bepresent,

[0006] X is —CO—R¹⁸—CO—, and if R¹—Q¹— or R²—Q²— is absent, R¹⁰, R¹³,R¹⁶, Het-CO or a fluorescent dye residue which is linked by way of a—CONH—, —COO—, —NH—C(═S)—NH—, —NH—C—(O)—NH—, —SO₂NH— or —NHCO— bond,

[0007] Z is, in each case independently of each other, an amino acidresidue or a di-, tri- or tetra-peptide residue, where the amino acidsare selected, independently of each other, from a group consisting ofAla, Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe,Pro, Ser, Thr, Trp, Tyr, Val or M,

[0008] where the said amino acids can also be derivatized and the aminoacid residues are linked to each other, in peptide manner, by way of theα-amino and α-carboxyl groups, and

[0009] where M is always present,

[0010] M is NH(R⁸)—CH(R³)—COOH,

[0011] R³ is —R⁵—R⁴, —R⁶—R⁴ or —R⁷—R⁴,

[0012] R⁴ is OH, NH₂, SH or COOH,

[0013] R⁵ is alkylene having 1-6 carbon atoms,

[0014] R⁶ is alkylenephenylene having 7-14 carbon atoms,

[0015] R⁷ is alkylenephenylalkylene having 8-15 carbon atoms,

[0016] R⁸ is H, A or alkylenephenyl having 7-12 carbon atoms,

[0017] A is alkyl having 1-6 carbon atoms,

[0018] R¹⁰ is alkanoyl having 1-18 carbon atoms which is unsubstitutedor substituted once by COOH, COOA, SR¹¹ or NR¹²R^(12′),

[0019] R¹¹ is H or trityl, pyridyl-2-thio or alkylthio having 1-6 carbonatoms,

[0020] R¹², R^(12′) are, in each case independently of each other, H,alkyl having 1-8 carbon atoms or an amino-protecting group,

[0021] R¹³ is aroyl having 7-11 carbon atoms which is unsubstituted orsubstituted once or twice by alkyl having 1-6 carbon atoms, alkoxyhaving 1-4 carbon atoms, alkanoyl having 1-8 carbon atoms, Hal, SR¹⁴ orNR¹⁵R^(15′),

[0022] R¹⁴ is H or A,

[0023] R¹⁵, R^(15′) are, in each case independently of each other, H orA,

[0024] R¹⁶ is aralkanoyl having 7-19 carbon atoms which is unsubstitutedor substituted once, twice or three times in the aryl moiety by Hal,alkoxy having 1-6 carbon atoms or OH and in which the aryl moiety canalso be a

[0025] E is CH₂ or O,

[0026] D is carbonyl or [C(R¹⁷R^(17′))]_(m),

[0027] R¹⁷, R^(17′) are, in each case independently of each other, H orA,

[0028] R¹⁸ is absent, or

[0029] is R¹⁹, R²⁰, R¹⁹-R²⁰-R¹⁹, or phenylene which is unsubstituted orsubstituted once or twice by R⁵, where the chain length of R⁵ is in eachcase independent of each other,

[0030] R¹⁹ is alkylene having 1-8 carbon atoms, where 1 or 2 methylenegroups can be replaced by S, —CH═CH— or —C—C—,

[0031] R²⁰ is cycloalkylene having 3-7 carbon atoms,

[0032] Hal is F, Cl, Br or I,

[0033] Het is a mononuclear or binuclear saturated, unsaturated oraromatic heterocycle having from 1 to 4 N, O and/or S atoms, bonded viaN or C, which can be unsubstituted or substituted once, twice or threetimes by Hal, A, R³, NR⁴R^(4′), CN, NO₂ and/or carbonyl oxygen,

[0034] n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and

[0035] m is 1 or 2,

[0036] where, provided that the residues are residues of opticallyactive amino acids and amino acid derivatives, both the D and the Lforms are included, and the salts thereof.

[0037] Similar compounds of cyclic peptides are disclosed in DE 43 10643.

[0038] The invention was based on the object of discovering novelcompounds possessing valuable properties, in particular those compoundswhich can be used for preparing pharmaceuticals.

[0039] It was found that the compounds of the formula I, and theirsalts, possess very valuable pharmacological properties while being welltolerated. In particular, they act as integrin inhibitors, in whichconnection they particularly inhibit the interactions of the α_(v)-, β₃-or β₅-integrin receptors with ligands, such as the binding of fibrinogento the β₃-integrin receptor. The compounds exhibit particular activityin the case of the α_(v)β₃, α_(v)β₅ and α_(IIb)β₃ integrins and also theα_(v)β₁, α_(v)β₆ and α_(v)β₈ integrins. This effect can be demonstrated,for example, using the method described by J. W. Smith et al. in J.Biol. Chem. 265, 12267-12271 (1990). PC Brooks, R. A. Clark and D. A.Cheresh have reported, in Science 264, 569-71 (1994), that thedevelopment of angiogenesis depends on the interaction between vascularintegrins and extracellular matrix proteins.

[0040] The possibility of using a cyclic peptide to inhibit thisinteraction, and thereby initiate apoptosis (programmed cell death) ofangiogenic vascular cells, has been described by P. C. Brooks, A. M.Montgomery, M. Rosenfeld, R. A. Reisfeld, T.-Hu, G. Klier and D. A.Cheresh in Cell 79, 1157-64 (1994).

[0041] Compounds of the formula I, which block the interaction ofintegrin receptors and ligands, such as that of fibrinogen to thefibrinogen receptor (Glycoprotein IIb/IIIa), prevent, as GPIIb/IIIaantagonists, the spread of tumour cells as a result of metastasis. Thisis substantiated by the following observations:

[0042] The compounds can inhibit the binding of metalloproteinases tointegrines and thereby prevent the cells from being able to use theenzymatic activity of the proteinase. An example is provided by theability of a cyclo-RGD peptide to inhibit the binding of MMP 2 (matrixmetalloproteinase 2) to the vitro-nectin receptor α_(v)β₃, as describedin P. C. Brooks et al., Cell 85, 683-693 (1996).

[0043] The spread of tumour cells from a local tumour into the vascularsystem takes place by the formation of microaggregates (microthrombi) asa result of the interaction of the tumour cells with blood platelets.The tumour cells are shielded as a result of the protection afforded bythe microaggregate and are not recognized by the cells of the immunesystem. The microaggregates can settle on vessel walls, therebyfacilitating further penetration of tumour cells into the tissue. Sincethe formation of the microthrombi is mediated by the binding offibrinogen to the fibrinogen receptors on activated blood platelets, theGPIIa/IIIb antagonists can be regarded as effective inhibitors ofmetastasis.

[0044] The compounds of the formula I may be employed as pharmaceuticalactive compounds in human and veterinary medicine, in particular for theprophylaxis and/or therapy of thrombosis, myocardial infarct,arteriosclerosis, inflammations, stroke, angina pectoris, tumourdiseases, osteolytic diseases such as osteoporosis, pathologicallyangiogenic diseases such as inflammations, ophthalmological diseases,diabetic retinopathy, macular degeneration, myopia, ocularhistoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma,ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis,restenosis following angioplasty, viral infection, bacterial infection,fungal infection, in acute liver failure and for supporting the healingprocesses in wound healing.

[0045] The compounds of the formula I may be employed as substanceshaving an antimicrobial effect in operations in which biomaterials,implants, catheters or heart pacemakers are used. In this context, theyhave an antiseptic effect. The efficacy of the antimicrobial activitycan be demonstrated using the method described by P. Valentin-Weigund etal., in Infection and Immunity, 2851-2855 (1988).

[0046] The amino acid residue abbreviations which are cited in the abovetext and in that which follows represent the residues of the followingamino acids:

[0047] Abu 4-Aminobutyric acid

[0048] Aha 6-Aminohexanoic acid, 6-aminocaproic acid

[0049] Ala Alanine

[0050] Asn Asparagine

[0051] Asp Aspartic acid

[0052] Arg Arginine

[0053] Cys Cysteine

[0054] Dab 2,4-Diaminobutyric acid

[0055] Dap 2,3-Diaminopropionic acid

[0056] Gln Glutamine

[0057] Glp Pyroglutamic acid

[0058] Glu Glutamic acid

[0059] Gly Glycine

[0060] His Histidine

[0061] homo-Phe homo-Phenylalanine

[0062] Ile Isoleucine

[0063] Leu Leucine

[0064] Lys Lysine

[0065] Met Methionine

[0066] Nle Norleucine

[0067] Orn Ornithine

[0068] Phe Phenylalanine

[0069] Phg Phenylglycine

[0070] 4-Hal-Phe 4-Halo-phenylalanine

[0071] Pro Proline

[0072] Ser Serine

[0073] Thr Threonine

[0074] Trp Tryptophan

[0075] Tyr Tyrosine

[0076] Val Valine.

[0077] In addition, the abbreviations below have the following meanings:

[0078] Ac Acetyl

[0079] BOC tert-Butoxycarbonyl

[0080] CBZ or Z Benzyloxycarbonyl

[0081] DCCI Dicyclohexylcarbodiimide

[0082] DMF Dimethylformamide

[0083] EDCI N-Ethyl-N,N′-(dimethylaminopropyl) carbodiimide

[0084] Et Ethyl

[0085] FCA Fluoresceincarboxylic acid

[0086] FITC Fluorescein isothiocyanate

[0087] Fmoc 9-Fluorenylmethoxycarbonyl

[0088] FTH Fluorescein thiourea

[0089] HOBt 1-Hydroxybenzotriazole

[0090] Me Methyl

[0091] MBHA 4-Methylbenzhydrylamine

[0092] Mtr 4-Methoxy-2,3,6-trimethylphenylsulphonyl

[0093] HONSu N-Hydroxysuccinimide

[0094] OBut tert-Butyl ester

[0095] Oct Octanoyl

[0096] OMe Methyl ester

[0097] OEt Ethyl ester

[0098] POA Phenoxyacetyl

[0099] Sal Salicyloyl

[0100] TFA Trifluoroacetic acid

[0101] Trt Trityl (triphenylmethyl).

[0102] Provided that the abovementioned amino acids are able to appearin several enantiomeric forms, all these forms, and also their mixtures(for example the DL forms) are included both above and below, forexample as an integral part of the compounds of the formula I. Inaddition, the amino acids can, for example as an integral part ofcompounds of the formula I, be provided with appropriate protectinggroups which are known per se.

[0103] The compounds according to the invention also include so-calledprodrug derivatives, that is compounds of the formula I which aremodified with, for example, alkyl or acyl groups, sugars oroligopeptides, and which are rapidly cleaved in the organism to give theeffective compounds according to the invention. This also includesbiodegradable polymer derivatives of the compounds according to theinvention, as described, for example, in Int. J. Pharm. 115, 61-67(1995).

[0104] The invention furthermore relates to a process for preparingcompounds of the formula I according to claim 1, and their salts,characterized in that

[0105] (a) a compound of the formula II

H—Q¹—R¹   II

[0106]  in which

[0107] Q¹ and R¹ have the meaning given in claim 1, is reacted, in anacylation reaction,

[0108] with a compound of the formula III

[0109] II [sic]

X—L   III

[0110]  in which

[0111] X has the meaning given in claim 1, and

[0112] L is Cl, Br, I or a free or reactive functionally modified OHgroup, or

[0113] b) in that a compound of the formula IV

H—Q²—R²   IV

[0114]  in which

[0115] Q² and R² have the meaning given in claim 1, is reacted, in anacylation reaction, with a compound of the formula V

R¹—Q¹—X—L   V

[0116]  in which

[0117] R¹, Q¹, X and L have the given meaning, or

[0118] c) in that a compound of the formula II

H—Q¹—R¹   II

[0119]  in which

[0120] Q¹and R¹ have the meaning given in claim 1,

[0121] is reacted, in an addition reaction, with a compound of theformula VI

X—U   VI

[0122] in which

[0123] X has the meaning given in claim 1, and

[0124] U is —N═C═O, —N═C═S or maleimidyl,

[0125] or

[0126] d) in that they are liberated from one of their functionalderivatives by treatment with a solvolysing or hydrogenolysing agent,

[0127] and/or in that a basic or acidic compound of the formula I isconverted into one of its salts by treatment with an acid or base.

[0128] In the above text, and in that which follows, the radicals Q¹,Q², R¹, R², X and L have the meanings given in the formulae I, II andIII provided another alternative is not expressly indicated.

[0129] In the above formulae, alkyl is preferably methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and, in addition,also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, or 1,1,2- or1,2,2-trimethylpropyl.

[0130] Alkylene is preferably methylene, ethylene, propylene, butylene,pentylene or hexylene. Alkylenephenyl is preferably benzyl or phenethyl.Alkylenephenylalkylene is preferably 4-methylenebenzyl or4-ethylenebenzyl.

[0131] Q¹ and Q² are preferably, in each case independently of eachother, 6-aminohexanoic acid (6-aminocaproic acid) or are absent, where,preferably, for example Q¹ is 6-aminohexanoic acid and Q² is absent.

[0132] M is preferably Dap, Ser, Cys, Asp, D-Asp, Dab, homoserine,homocysteine, Glu, D-Glu, Thr, Orn, Lys, D-Lys, 4-aminomethyl-Phe or4-aminomethyl-D-Phe.

[0133] The amino acids and amino acid residues which are mentioned for Zin the meanings can also be derivatized, with the N-methyl, N-ethyl,N-propyl, N-benzyl or C_(α)-methyl derivatives being preferred.Preference is also given to derivatives of Asp and Glu, in particularthe methyl, ethyl, propyl, butyl, tert-butyl, neopentyl or benzyl estersof the side-chain carboxyl groups, and also to derivatives of Arg, whichcan be substituted on the —NH—C(═NH)—NH₂ group by an acetyl, benzoyl,methoxycarbonyl or ethoxycarbonyl radical.

[0134] Z is preferably M, with preference also being given to D-Phe-M,D-Trp-M, D-Tyr-M, D-Phe-Lys, D-Phe-D-Lys, D-Trp-Lys, D-Trp-D-Lys,D-Tyr-Lys, D-Tyr-D-Lys, D-Phe-Orn, D-Phe-Dab, D-Phe-Dap, D-Phe-D-Orn,D-Phe-D-Dab, D-Phe-D-Dap, D-Phe-4-aminomethyl-Phe,D-Phe-4-aminomethyl-D-Phe, D-Trp-4-aminomethyl-Phe,D-Trp-4-aminomethyl-D-Phe, D-Tyr-4-aminomethyl-Phe,D-Tyr-4-aminomethyl-D-Phe, D-Phe-Asp, D-Phe-D-Asp, D-Trp-Asp,D-Trp-D-Asp, D-Tyr-Asp, D-Tyr-D-Asp, D-Phe-Cys, D-Phe-D-Cys, D-Trp-Cys,D-Trp-D-Cys, D-Tyr-Cys, D-Tyr-D-Cys, Phe-D-Lys, Trp-D-Lys, Tyr-D-Lys,Phe-Orn, Phe-Dab, Phe-Dap, Trp-Orn, Trp-Dab, Trp-Dap, Tyr-Orn, Tyr-Dab,Tyr-Dap, Phe-4-aminomethyl-D-Phe, Trp-4-aminomethyl-D-Phe,Tyr-4-aminomethyl-D-Phe, Phe-D-Asp, Trp-D-Asp, Tyr-D-Asp, Phe-D-Cys,Trp-D-Cys, Tyr-D-Cys, D-Phe-Lys-Gly, D-Phe-M-Gly, D-Trp-Lys-Gly,D-Trp-M-Gly, D-Tyr-Lys-Gly, D-Tyr-M-Gly, D-Phe-Val-Lys, D-Phe-Gly-Lys,D-Phe-Ala-Lys, D-Phe-Ile-Lys, D-Phe-Leu-Lys, D-Trp-Val-Lys,D-Trp-Gly-Lys, D-Trp-Ala-Lys, D-Trp-Ile-Lys, D-Trp-Leu-Lys,D-Tyr-Val-Lys, D-Tyr-Gly-Lys, D-Tyr-Ala-Lys, D-Tyr-Ile-Lys,D-Tyr-Leu-Lys, and also M-Pro-Ala-Ser-Ser.

[0135] The radical —R⁶—R⁴ is preferably 2-, 3- or 4-hydroxybenzyl, 2-,3- or 4-aminobenzyl, 2-, 3- or 4-mercaptobenzyl, 2-, 3- or4-carboxybenzyl, and also, preferably, 2-, 3- or 4-hydroxyphenethyl, 2-,3- or 4-aminophenethyl, 2-, 3- or 4-mercaptophenethyl or 2-, 3- or4-carboxyphenethyl.

[0136] Alkanoyl is preferably formyl, acetyl, propionyl, butyryl,pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl,undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl,hexadecanoyl, heptadecanoyl or octadecanoyl.

[0137] Aroyl is preferably benzoyl or naphthoyl.

[0138] R¹³ is unsubstituted, preferably—as indicated—monosubstitutedbenzoyl, with individual preference being given to benzoyl, o-, m- orp-methylbenzoyl, o-, m- or p-ethylbenzoyl, o-, m- or p-propylbenzoyl,o-, m- or p-isopropylbenzoyl, o-, m- or p-tert-butylbenzoyl, o-, m- orp-aminobenzoyl, o-, m- or p-(N-methylamino)-benzoyl, o-, m- orp-methoxybenzoyl, o-, m- or p-ethoxybenzoyl, o-, m- orp-(N,N,dimethylamino)-benzoyl, o-, m- or p-(N-ethylamino)-benzoyl, o-,m- or p-(N,N-diethylamino)-benzoyl, o-, m- or p-fluorobenzoyl, o-, m- orp-bromobenzoyl, o-, m- or p-chlorobenzoyl, o-, m- or p-formylbenzoyl,o-, m- or p-acetylbenzoyl, o-, m- or p-propionylbenzoyl, o-, m- orp-butyrylbenzoyl, o-, m- or p-pentanoylbenzoyl, o-, m- orp-methylthiobenzoyl, with preference also being given to 2,3-, 2,4-,2,5-, 2,6-, 3,4- or 3,5-difluorobenzoyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorobenzoyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromobenzoyl,2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-,2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-,2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-,3-chloro-5-methyl- or 3-methyl-4-chlorobenzoyl, 2-bromo-3-methyl-,2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-,2-methyl-3-bromo-, 2-methyl-4-bromo-, 2-methyl-5-bromo-,2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5-methyl- or3-methyl-4-bromobenzoyl, or 2,5- or 3,4-dimethoxybenzoyl.

[0139] R¹⁶ is unsubstituted, preferably—as indicated—monosubstitutedphenylacetyl, with individual preference being given to phenylacetyl,o-, m- or p-methoxyphenylacetyl, o-, m- or p-hydroxyphenylacetyl, o-, m-or p-ethoxyphenylacetyl, o-, m- or p-fluorophenylacetyl, o-, m- orp-bromophenylacetyl, o-, m- or p-chlorophenylacetyl, with preferencealso being given to 3-phenylpropionyl, 4-phenylbutyryl,5-phenylpentanoyl, 6-phenylhexanoyl, 7-phenylheptanoyl,8-phenyloctanoyl, 9-phenylnonanoyl, 10-phenyldecanoyl,11-phenylundecanoyl, 12-phenyldodecanoyl or 13-phenyltridecanoyl, and,in addition, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxobenzofuranyl.

[0140] Cycloalkylene is preferably cyclopropylene, 1,2- or1,3-cyclobutylene, 1,2- or 1,3-cyclopentylene, 1,2-, 1,3- or1,4-cyclohexylene and, in addition, 1,2-, 1,3- or 1,4-cycloheptylene.

[0141] D is preferably CH₂, with carbonyl also being preferred.

[0142] Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, andpreferably also 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3-or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3-or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6-or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-,5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-,4-, 5-, 6-, 7- or 8-cinnolinyl or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.The heterocyclic radicals can also be partially or completelyhydrogenated. Het can consequently also, for example, be 2,3-dihydro-2-,-3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl,tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or-3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl,tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5-, -6-, -7- or -8-isoquinolyl.

[0143] Amino-protecting group is preferably acetyl, propionyl, butyryl,phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ(“carbobenzoxy”), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.

[0144] Fluorescent dye residue is preferably 7-acetoxycoumarin-3-yl,fluorescein-5-(and/or 6-)yl, 2′,7′-dichlorofluorescein-5-(and 6-)yl,dihydrotetramethylrosamin-4-yl, tetramethylrhodamin-5-(and/or 6-)yl,4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacen-3-ethyl or4,4-difluoro-5,7-diphenyl-4-bora-3a,4a-diaza-s-indacen-3-ethyl.

[0145] Suitable functionalized fluorescent dye residues which can beused as reagents for preparing the compounds according to the inventionof the formula I are described, for example, in Handbook of FluorescentProbes and Research Chemicals, 5th Edition, 1992-1994 by R. P.Haughland, Molecular Probes, Inc.

[0146] m is preferably 1, with 2 also being preferred.

[0147] Hal is preferably F, Cl or Br, and also I.

[0148] The compounds of formula I may possess one or more chiral centresand therefore occur in different stereoisomeric forms. The formula Iencompasses all these forms.

[0149] Accordingly, the invention relates, in particular, to thosecompounds of the formula I in which at least one of the said radicalshas one of the abovementioned preferred meanings. Some preferred groupsof compounds may be expressed by the following partial formulae Ia toIh, which correspond to the formula I and in which the radicals whichare not specifically named have the meaning given in formula I, but inwhich

[0150] in a)

[0151] Q¹, Q² and R² are absent,

[0152] R¹ is cyclo-(Arg-Gly-Asp-Z), and

[0153] X is alkanoyl;

[0154] in b)

[0155] Q¹, Q² and R² are absent,

[0156] R¹ is cyclo-(Arg-Gly-Asp-M), and

[0157] X is alkanoyl;

[0158] in c)

[0159] Q¹, Q² and R² are absent,

[0160] R¹ is cyclo-(Arg-Gly-Asp-D-Phe-Lys), and

[0161] X is alkanoyl;

[0162] in d)

[0163] Q¹ and Q² are absent,

[0164] R¹ and R² are cyclo-(Arg-Gly-Asp-D-Phe-Lys), and

[0165] X is —CO—(CH₂)_(n)—CO—;

[0166] in e)

[0167] Q² and R² are absent,

[0168] Q¹ is —NH—(CH₂)₅—CO—,

[0169] R¹ is cyclo-(Arg-Gly-Asp-Z), and

[0170] X is a fluorescent dye residue;

[0171] in f)

[0172] Q² and R² are absent,

[0173] Q¹ is —NH—(CH₂)₅—CO—,

[0174] R¹ is cyclo-(Arg-Gly-Asp-M), and

[0175] X is fluoresceinoyl;

[0176] in g)

[0177] Q¹ and Q² are absent,

[0178] R¹ and R² are cyclo-(Arg-Gly-Asp-M), and

[0179] X is —CO—(CH₂)₈—CO—;

[0180] in h)

[0181] Q¹, Q² and R² are absent,

[0182] R¹ is cyclo-(Arg-Gly-Asp-Z), and

[0183] X is CH₃—(CH₂)₁₆—CO—.

[0184] Particular preference is given to compounds of the formula VII

Cyclo-(Arg-Gly-Asp-D-Phe-Lys(Q¹-X)   VII,

[0185] in which Q¹ has the meaning given in claim 1, and where Q¹ isbonded to the side chain of the lysine, or, if Q¹ is absent, X is bondedto the side chain of the lysine, and in which X is preferably

[0186] alkanoyl having 1-18 carbon atoms which is unsubstituted orsubstituted once by COOH, COOA, SR¹⁴ or NR¹⁵R^(15′), FCA or FTH,

[0187] or aroyl having 7-11 carbon atoms which is unsubstituted orsubstituted once or twice by alkyl having 1-6 carbon atoms, alkoxyhaving 1-4 carbon atoms, alkanoyl having 1-8 carbon atoms, Hal, SR¹⁴ orNR¹⁵R^(15′), where R¹⁴, R¹⁵ and R^(15′) have the meanings given in claim1.

[0188] Otherwise, the compounds of the formula I, and also the startingcompounds for preparing them, are prepared by methods which are knownper se, as described in the literature (for example in the standardworks such as Houben-Weyl, Methoden der organischen Chemie, [Methods oforganic chemistry], Georg-Thieme-Verlag, Stuttgart;) specifically underreaction conditions which are known and suitable for the said reactions.In this context, use can also be made of variants which are known per sebut which are not detailed here.

[0189] The starting compounds can, if desired, also be formed in situ,so that they are not isolated from the reaction mixture but, instead,immediately subjected to further reaction to give the compounds of theformula I.

[0190] Compounds of the formula I may preferably be obtained by reactingcompounds of the formula II with compounds of the formula III.

[0191] As a rule, the compounds of the formula [sic] II and III areknown. If they are not known, they can be prepared by methods which areknown per se.

[0192] In the compounds of the formula III, the radical L is preferablya preactivated carboxylic acid, preferably a carbonyl halide,symmetrical or mixed anhydride or an active ester. Radicals of thisnature for activating the carboxyl group in typical acylation reactionsare described in the literature (for example in the standard works suchas Houben-Weyl, Methoden der organischen Chemie [Methods of organicchemistry], Georg-Thieme-Verlag, Stuttgart). Activated esters areexpediently formed in situ, for example by adding HOBt orN-hydroxysuccinimide.

[0193] L is preferably H, F, Cl, Br or —ON— succinimide.

[0194] As a rule, the reaction is carried out in an inert solvent in thepresence of an acid-binding agent, preferably an organic base such astriethylamine, dimethylaniline, pyridine or quinoline, or of an excessof the carboxyl component of the formula III. It can also beadvantageous to add an alkali metal or alkaline earth metal hydroxide,carbonate or bicarbonate or another salt of a weak acid of the alkalimetals or alkaline earth metals, preferably of potassium, sodium,calcium or caesium. In each case depending on the conditions used, thereaction time is between a few minutes and 14 days, while the reactiontemperature is between about −30° and 140°, normally between −10° and90°, in particular between about 0° and about 70°.

[0195] Examples of suitable inert solvents are hydrocarbons such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbontetrachloride, chloroform or dichloromethane; alcohols such as methanol,ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers such as ethylene glycol monomethyl ether or ethyleneglycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycoldimethyl ether (diglyme); ketones such as acetone or butanone; amidessuch as acetamide, dimethylacetamide or dimethylformamide (DMF);nitriles such as acetonitrile; sulphoxides such as dimethyl sulphoxide(DMSO); carbon disulphide; carboxylic acids such as formic acid oracetic acid; nitro compounds such as nitromethane or nitrobenzene;esters such as ethyl acetate, water, or mixtures of the said solvents.

[0196] In addition, compounds of the formula I can be obtained byreacting compounds of the formula IV with compounds of the formula V. Asa rule, the starting compounds of the formula IV and V are known. Ifthey are not known, they can be prepared by methods which are known perse.

[0197] In the compounds of the formula V, the radical L is preferably apreactivated carboxylic acid, preferably a carbonyl halide, symmetricalor mixed anhydride or an active ester. Radicals of this nature foractivating the carboxyl group in typical acylation reactions aredescribed in the literature (for example in the standard works such asHouben-Weyl, Methoden der organischen Chemie, [Methods of organicchemistry], Georg-Thieme-Verlag, Stuttgart). L is preferably F, Cl, Bror —ON— succinimide.

[0198] The reaction of the compounds of the formula IV with compounds ofthe formula V is carried out under the same conditions, as regards thereaction time, the temperature and the solvent, as has been describedfor the reaction of the compounds of the formula II with compounds ofthe formula III.

[0199] In addition, compounds of the formula I can be obtained byreacting compounds of the formula II with compounds of the formula VI.As a rule, the starting compounds of the formula [sic] II and VI areknown. If they are not known, they can be prepared by methods which areknown per se.

[0200] The reaction of compounds of the formula II with compounds of theformula III constitutes a typical addition to isothiocyanates. Additionsof this nature are described in the literature (for example in thestandard works such as Houben-Weyl, Methoden der organischen Chemie[Methods of organic chemistry], Georg-Thieme-Verlag, Stuttgart).

[0201] Cyclic compounds of the formula R¹ and/or R² can be prepared bycyclizing the linear compounds as, for example, described in DE 43 10643 or in Houben-Weyl, I.c., Volume 15/II, pages 1 to 806 (1974).

[0202] The compounds of the formula I can furthermore be obtained byliberating them from their functional derivatives by means ofsolvolysis, in particular hydrolysis, or by hydrogenolysis.

[0203] Starting compounds which are preferred for the solvolysis orhydrogenolysis are those which, in place of one or more free aminoand/or hydroxyl groups, contain corresponding, protected amino and/orhydroxyl groups, preferably those which carry an amino protecting groupin place of an H atom which is bonded to an N atom, for example thosewhich conform to the formula I but which contain an NHR′ group (in whichR′ is an amino protecting group, for example BOC or CBZ) in place of anNH₂ group.

[0204] In addition, starting compounds are preferred which carry anhydroxyl-protecting group in place of the H atom of an hydroxyl group,for example those which conform to the formula I but which contain anR″O-phenyl group (in which R″ is an hydroxyl-protecting group) in placeof an hydroxyphenyl group.

[0205] Several—identical or different—protected amino and/or hydroxylgroups can also be present in the molecule of the starting compound. Ifthe protecting groups which are present are different from each other,they can in many cases be eliminated selectively.

[0206] The expression “amino-protecting group” is well known and relatesto groups which are suitable for protecting (blocking) an amino groupfrom chemical reactions but which can readily be removed after thedesired chemical reaction has been carried out at other sites in themolecule. Unsubstituted or substituted acyl, aryl, aralkoxymethyl oraralkyl groups are typical groups of this nature. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their nature and size is otherwise not critical;however, those having 1-20, in particular 1-8, carbon atoms arepreferred. In connection with the present process, the expression “acylgroup” is to be understood in the broadest possible sense. It comprisesacyl groups which are derived from aliphatic, araliphatic, aromatic orheterocyclic carboxylic acids or sulphonic acids, and also, inparticular, alkoxycarbonyl, aryloxycarbonyl and, especially,aralkoxycarbonyl groups. Examples of acyl groups of this nature arealkanoyl such as acetyl, propionyl and butyryl; aralkanoyl such asphenylacetyl; aroyl such as benzoyl or tolyl; aryloxyalkanoyl such asPOA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, BOC or 2-iodoethoxycarbonyl;aralkyloxycarbonyl such as CBZ (“carbobenzoxy”),4-methoxybenzyloxycarbonyl or FMOC; arylsulphonyl such as Mtr. Thoseamino-protecting groups which are preferred are BOC and Mtr, and alsoCBZ, Fmoc, benzyl and acetyl.

[0207] The expression “hydroxyl-protecting group” is likewise well knownand refers to groups which are suitable for protecting an hydroxyl groupfrom chemical reactions but which can readily be removed after thedesired chemical reaction has been carried out at other sites in themolecule. The abovementioned unsubstituted or substituted aryl, aralkylor acyl groups, and also alkyl groups, are typical groups of thisnature. The nature and size of the hydroxyl-protecting groups is notcritical since the groups are removed once again after the desiredchemical reaction or reaction sequence; groups having 1-20, inparticular 1-10, carbon atoms are preferred. Examples ofhydroxyl-protecting groups are, inter alia, benzyl, p-nitrobenzoyl,p-toluenesulphonyl, tert-butyl and acetyl, with benzyl and tert-butylbeing particularly preferred. The COOH groups in aspartic acid andglutamic acid are preferably protected in the form of their tert-butylesters (for example Asp(OBut)).

[0208] The compounds of the formula I are—depending on the protectinggroup employed—liberated from their functional derivatives using, forexample, strong acids, expediently TFA or perchloric acid, but alsoother strong inorganic acids, such as hydrochloric acid or sulphuricacid, strong organic carboxylic acids, such as trichloroacetic acid, orsulphonic acids, such as benzenesulphonic acid or p-toluenesulphonicacid. It is possible, but not always necessary, for an additional inertsolvent to be present. Suitable inert solvents are preferably organic,for example carboxylic acids such as acetic acid, ethers such astetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbonssuch as dichloromethane, and also alcohols such as methanol, ethanol orisopropanol, and also water. Mixtures of the previously mentionedsolvents are also suitable. TFA is preferably used in excess withoutadding any other solvent, while perchloric acid is used in the form of amixture of acetic acid and 70% perchloric acid in a ratio of 9:1. Thereaction temperatures for the cleavage are expediently between about 0°and 50°, with the cleavage preferably being carried out at between 15and 30° or room temperature.

[0209] The BOC, OBut and Mtr groups can preferably be eliminated, forexample, using TFA in dichloromethane or using approximately 3 to 5n HClin dioxane at 15-30°, while the FMOC group can preferably be eliminatedusing an approximately 5 to 50% solution of dimethylamine, diethylamineor piperidine in DMF at 15-30°.

[0210] The trityl group is employed for protecting the amino acidshistidine, asparagine, glutamine and cysteine. Depending on the desiredend product, it is eliminated using TFA/10% thiophenol, with the tritylgroup being eliminated from all the said amino acids; when TFA/anisoleor TFA/thioanisole is used, the trityl group is only eliminated fromHis, Asn and Gln, whereas it remains on the Cys side chain.

[0211] Hydrogenolytically removable protecting groups (for example CBZor benzyl) can, for example, be eliminated by treating with hydrogen inthe presence of a catalyst (for example a precious metal catalyst suchas palladium, expediently on a support such as carbon). Suitablesolvents in this context are the abovementioned solvents, in particular,for example, alcohols such as methanol or ethanol or amides such as DMF.As a rule, the hydrogenolysis is carried out at temperatures of betweenabout 0 and 100° and pressures of between 1 and 200 bar, preferably at20-30° and 1-10 bar. The CBZ group is satisfactorily eliminatedhydrogenolytically on 5 to 10% Pd/C in methanol or using ammoniumformate (in place of hydrogen) on Pd/C in methanol/DMF at 20-30°.

[0212] A base of the formula I can be converted with an acid into theassociated acid addition salt, for example by reacting equivalentquantities of the base and the acid in an inert solvent such as ethanoland then concentrating by evaporation. Suitable acids for this reactionare, in particular, those which give rise to physiologically harmlesssalts. Thus, use can be made of inorganic acids, for example sulphuricacid, nitric acid, hydrohalic acids such as hydrochloric acid orhydrobromic acid, phosphoric acids such as orthophosphoric acid, andsulphamic acid, and, in addition, organic acids, in particularaliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic orpolybasic carboxylic, sulphonic or sulphuric acids, for example formicacid, acetic acid, propionic acid, pivalic acid, diethylacetic acid,malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid,lactic acid, tartaric acid, malic acid, citric acid, gluconic acid,ascorbic acid, nicotinic acid, isonicotinic acid, methanesulphonic acid,ethanesulphonic acid, ethanedisulphonic acid, 2-hydroxyethanesulphonicacid, benzenesulphonic acid, p-toluenesulphonic acid,naphthalenemonosulphonic acid, naphthalenedisulphonic acid and laurylsulphuric acid. Salts with acids which are not physiologically harmless,for example picrates, may be used for isolating and/or purifying thecompounds of the formula I.

[0213] On the other hand, an acid of the formula I can be converted intoone of its physiologically harmless metal or ammonium salts by reactionwith a base. In this context, the sodium, potassium, magnesium, calciumand ammonium salts are particularly suitable as salts, as are alsosubstituted ammonium salts, for example the dimethyl-, diethyl- ordiisopropylammonium salts, monoethyl-, diethyl- or diisopropylammoniumsalts, cyclohexyl- and dicyclohexylammonium salts, anddibenzylethylenediammonium salts, and also, for example, salts witharginine or lysine.

[0214] The invention furthermore relates to the use of the compounds ofthe formula I and/or their physiologically harmless salts for producingpharmaceutical preparations, in particular by a non-chemical route. Inthis context, they can be brought into a suitable dosage form togetherwith at least one solid, liquid and/or semisolid carrier substance orauxiliary substance and, where appropriate, in combination with one ormore additional active compounds.

[0215] The invention furthermore relates to pharmaceutical preparationswhich contain at least one compound of the formula I and/or one of itsphysiologically harmless salts.

[0216] These preparations may be used as pharmaceuticals in human andveterinary medicine. Suitable carrier substances are organic orinorganic substances which are suitable for enteral (for example oral),parenteral or topical administration or for administration in the formof an inhalation spray and which do not react with the novel compounds,for example water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatin, carbohydrates suchas lactose or starch, magnesium stearate, talc or vaseline. For oralemployment, use is made, in particular, of tablets, pills, coatedtablets, capsules, powders, granules, syrups, juices or drops, forrectal employment of suppositories, for parenteral employment ofsolutions, preferably oily or aqueous solutions, and also suspensions,emulsions or implants, and, for topical employment, of ointment, creamsor powders. The novel compounds can also be lyophilized and theresulting lyophilizates used, for example, for producing injectionpreparations. The preparations mentioned can be sterilized and/orcontain auxiliary substances such as lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing theosmotic pressure, buffering substances, dyes, flavourings and/or severaladditional active compounds, for example one or more vitamins. Foradministration as an inhalation spray, sprays can be used which containthe active compound either dissolved or suspended in a propellant gas orpropellant gas mixture (for example CO₂ or fluorochlorohydrocarbons). Inthis context, the active compound is expediently used in micronizedform, with it being possible for one or more additional physiologicallytolerated solvents, for example ethanol, to be present. Inhalationsolutions can be administered using customary inhalers.

[0217] The compounds of the formula I and their physiologically harmlesssalts may be used as integrin inhibitors in the control of diseases, inparticular pathologically angiogenic diseases, thromboses, cardiacinfarct, coronary heart diseases, arteriosclerosis, tumours,osteoporosis, inflammations and infections.

[0218] In this connection, the substances according to the inventioncan, as a rule, be administered in analogy with other known,commercially available peptides, in particular, however, in analogy withthe compounds described in U.S. Pat. No. 4,472,305, preferably indosages of between 0.05 and 500 mg, in particular between 0.5 and 100 mgper dosage unit. The daily dose is preferably between about 0.01 and 2mg/kg of body weight. However, the special dose for each patient dependson a very wide variety of factors, for example on the activity of thespecial compound employed, on age, body weight, general state of health,sex, diet, time and route of administration, the excretion rate,pharmaceutical combination and severity of the particular disease towhich the therapy applies. Parenteral administration is preferred.

[0219] In addition, the novel compounds of the formula I can be used inanalytical biology and molecular biology.

[0220] The novel compounds of the formula I, in which X is a fluorescentdye residue which is linked by way of a —CONH—, —COO—, —NH—C(═S)—NH—,—NH—C(═O)—NH—, —SO₂NH— or —NHCO— bond, can be used as diagnostic markersin FACS (fluorescence activated cell sorter) analysis and fluorescencemicroscopy.

[0221] The use of labelled compounds in fluorescence microscopy isdescribed, for example, by Y.-L. Wang and D. L. Taylor in “FluorescenceMicroscopy of Living Cells in Culture, Part A+B, Academic Press, Inc.1989”.

[0222] The novel compounds of the formula I may also be used in affinitychromatography for eluting bound proteins. In particular, they may beused as integrin ligands for eluting integrins.

[0223] Both in the above text and in that which follows all temperaturesare given in ° C. In the following examples, “customary working-up”denotes: water is added, if required, the pH is adjusted, if requiredand depending on the constitution of the end product, to values ofbetween 2 and 10, the mixture is extracted with ethyl acetate ordichloromethane, the phases are separated, the organic phase is driedover sodium sulphate and evaporated, and the residue is purified bychromatography on silica gel and/or by crystallization. Rf values onsilica gel; mobile phase: ethyl acetate/methanol 9:1.

[0224] RT=retention time (minutes) in HPLC in the following systems:

[0225] [A]

[0226] Column: Nucleosil 7C 18 250×4 mm

[0227] Eluent A: 0.1% TFA in water

[0228] Eluent B: 0.1% TFA in acetonitrile

[0229] Flow rate: 1 ml/min

[0230] Gradient: 20-50% B/30 min.

[0231] [B]

[0232] 50 minute gradient of 0-80% 2-propanol in water containing 0.3%TFA at 1 ml/min on a Lichrosorb® RP Select B (7 μm) 250×4 mm column

[0233] [C]

[0234] Column: Lichrospher (5 μm) 100 RP8 125×4 mm

[0235] Eluent A: 0.1 M Na phosphate pH 7.0

[0236] Eluent B: 0.005 M Na phosphate, pH 7.0/60 vol % of 2-propanol

[0237] Flow rate: 0.7 ml/min

[0238] Gradient: 1-99% B/50 min.

[0239] Mass spectrometry (MS):

[0240] EI(electron collision ionization) M⁺

[0241] FAB (fast atom bombardment) (M+H)⁺

EXAMPLE 1

[0242] 1.0 g of O-acetyl salicylic acid N-succinimidyl ester [obtainableby reacting acetylsalicylic acid with HONSu in ethyl acetate, DMF and1.2 equivalents of diisopropylcarbodiimide, FAB 278] and 0.5 g oftriethylamine are added to a solution of 3.05 g ofcyclo-(Arg-Gly-Asp-D-Phe-Lys) [obtainable by cyclizingH-Arg(Mtr)-Gly-Asp(OBut)-D-Phe-Lys(BOC)-OH to givecyclo-(Arg(Mtr)-Gly-Asp(OBut)-D-Phe-Lys(BOC)) and then eliminating theprotecting groups] in 100 ml of DMF. The mixture is stirred at roomtemperature for 5 hours, andcyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-Sal))×TFA; RT[B] 22.0; FAB 724 isobtained after the customary working-up and with the concomitantelimination of the acetyl group.

[0243] The following are obtained in an analogous manner by reactingcyclo-(Arg-Gly-Asp-D-Phe-Lys)

[0244] with phenylpropionic acid N-succinimidyl ester (PhEtCO-ONSu):

[0245] cyclo-(Arg-Gly-Asp-D-Phe-Lys (N⁶⁸ -PhEtCo))×TFA; RT [C] 28.2; FAB736;

[0246] with 3,3,3-tris-(4-chlorophenyl)-propionic acid N-succinimidylester (TCPP-ONSu):

[0247] cyclo-(Arg-Gly-Asp-D-Phe-Lys(N⁶⁸ -TCPP))×TFA; RT [B] 33.19; FAB992;

[0248] with S-tritylmercaptopropionic acid N-succinimidyl ester(TrtSEtCO-ONSu):

[0249] cyclo-(Arg-Gly-Asp-D-Phe)Lys (N^(ε)TrtSEtCO))×TFA; RT [B] 33.4;FAB 934;

[0250] with benzyloxycarbonyl chloride (CBZ-Cl):

[0251] cyclo-(Arg-Gly-Asp-D-Phe-Lys (N⁶⁸ -CBZ));

[0252] with octanoyl anhydride:

[0253] cyclo-(Arg-Gly-Asp-D-Phe-Lys(N⁶⁸ -Oct))×TFA; RT [B] 27.58; FAB730;

[0254] with acetic anhydride:

[0255] cyclo-(Arg-Gly-Asp-D-Phe-Lys (N^(ε)-Ac))×TFA; RT [B] 17.02; FAB646;

[0256] with FCA-N-succinimidyl ester:

[0257] cyclo-((Arg-Gly-Asp-D-Phe-Lys (N⁶⁸ -FCA)) RT [B] 24.18; FAB 962;

[0258] with FITC:

[0259] cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-FTH))×TFA; RT [B] 27.3; FAB994,

[0260] from which the internal salt can be obtained using NH4HCO3, RT[B] 22.26;

[0261] The following are obtained in an analogous manner by reactingcyclo-(Arg-Gly-Asp-D-Phe-N-Me-Lys)

[0262] with FITC:

[0263] cyclo-(Arg-Gly-Asp-D-Phe-N (Me)-Lys (N^(ε)-FTH)); RT [B] 22.64;FAB 1007;

[0264] with benzyloxycarbonyl chloride (CBZ-Cl):

[0265] cyclo-(Arg-Gly-Asp-D-Phe-N(Me)-Lys (N⁶⁸ -CBZ)); RT 23.35; FAB752.

EXAMPLE 2

[0266] 6 g of BOC-Aha-N-succinimidyl ester are added to a solution of3.05 g of cyclo-(Arg-Gly-Asp-D-Phe-Lys) in 40 ml of 5% aqueous NaHCO₃and 40 ml of THF. The mixture is stirred for 4 hours and worked-up inthe customary manner, affording cyclo-(Arg-Gly-Asp-D-Phe-Lys(BOC-Aha));RT [C] 27.7; FAB 817. After the BOC group has been eliminated inHCl/dioxane, cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-Aha))×2 TFA; RT [C]14.76; FAB 717 is obtained after the customary working-up.Cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-FCA-Aha))×TFA; RT [B] 23.8; FAB 1075is obtained, in analogy with Example 1, by subsequent reaction withFCA-N-succinimidyl ester.

[0267] The following are obtained in an analogous manner by reactingcyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-Aha))

[0268] with FITC:

[0269] cyclo-(Arg-Gly-Asp-D-Phe-Lys (N^(ε)-FTH-Aha))

[0270] with acetic anhydride:

[0271] cyclo-(Arg-Gly-Asp-D-Phe-Lys (N^(ε)-Ac-Aha))×TFA; RT [B] 17.1;FAB 759;

EXAMPLE 3

[0272] In analogy with Example 2,cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-BOC-Aha)-Gly) is obtained fromcyclo-(Arg-Gly-Asp-D-Phe-Lys-Gly) [obtainable by cyclizingH-Arg(Mtr)-Gly-Asp(OBut)-D-Phe-Lys(BOC)-Gly-OH to givecyclo-(Arg(Mtr)-Gly-Asp(OBut)-D-Phe-Lys(BOC)-Gly) and then eliminatingthe protecting groups] and BOC-Aha-N-succinimidyl ester;

[0273] After eliminating the BOC group in HCl/dioxane,cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-Aha)-Gly)×2 TFA is obtained after thecustomary working-up.

[0274] The following is obtained, in analogy with Example 1, bysubsequently reacting cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-Aha)-Gly×2 TFAwith phenylpropionic acid N-succinimidyl ester:

[0275] Cyclo-(Arg-Gly-Asp-D-Phe-Lys (N^(ε)-PhEtCO-Aha)-Gly).

[0276] The following are obtained in an analogous manner by reactingcyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-Aha)-Gly)

[0277] with octanoyl anhydride:

[0278] Cyclo-(Arg-Gly-Asp-D-Phe-Lys (N^(ε)-Oct-Aha)-Gly)

[0279] with FCA-N-succinimidyl ester:

[0280] Cyclo-(Arg-Gly-Asp-D-Phe-Lys (N^(ε)-FCA-Aha)-Gly)

[0281] with FITC:

[0282] Cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-FTH-Aha)-Gly).

[0283] In analogy with Example 2,cyclo-(Arg-Gly-Asp-D-Phe-Val-Lys-(N^(ε)-BOC-Aha))×TFA is obtained fromcyclo-(Arg-Gly-Asp-D-Phe-Val-Lys) [obtainable by cyclizingH-Arg(Mtr)-Gly-Asp(OBut)-D-Phe-Val-Lys(BOC)-OH to givecyclo-(Arg(Mtr)-Gly-Asp(OBut)-D-Phe-Val-Lys(BOC)) and then eliminatingthe protecting groups] and BOC-Aha-N-succinimidyl ester.

[0284] After the BOC group is eliminated in HCl/dioxane,cyclo-(Arg-Gly-Asp-D-Phe-Val-Lys(N^(ε)-Aha))×2 TFA is obtained after thecustomary working-up.

[0285] In analogy with Example 1,cyclo-(Arg-Gly-Asp-D-Phe-Val-Lys(N^(ε-)PhEtCo-Aha)) is obtained bysubsequently reacting cyclo-(Arg-Gly-Asp-D-Phe-Val-Lys (N^(ε)-Aha))×2TFA with phenylpropionic acid N-succinimidyl ester.

EXAMPLE 4

[0286] In analogy with Example 2, reaction of BOC-aminocaproic acidN-succinimidyl ester with the following cyclic compounds

[0287] Cyclo-(Arg-Gly-Asp-D-Trp-Lys)

[0288] Cyclo-(Arg-Gly-Asp-D-Tyr-Lys)

[0289] Cyclo-(Arg-Gly-Asp-D-Phe-D-Lys)

[0290] Cyclo-(Arg-Gly-Asp-D-Phe-Cys)

[0291] Cyclo-(Arg-Gly-Asp-D-Phe-Dab)

[0292] Cyclo-(Arg-Gly-Asp-D-Trp-D-Cys)

[0293] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Cys)

[0294] Cyclo-(Arg-Gly-Asp-Phe-D-Lys)

[0295] Cyclo-(Arg-Gly-Asp-Trp-D-Lys)

[0296] Cyclo-(Arg-Gly-Asp-Tyr-D-Lys)

[0297] Cyclo-(Arg-Gly-Asp-Phe-D-Cys)

[0298] Cyclo-(Arg-Gly-Asp-Phe-Dab)

[0299] Cyclo-(Arg-Gly-Asp-Trp-D-Cys)

[0300] Cyclo-(Arg-Gly-Asp-Tyr-D-Cys)

[0301] Cyclo-(Arg-Gly-Asp-D-Trp-Orn)

[0302] Cyclo-(Arg-Gly-Asp-D-Tyr-Orn)

[0303] Cyclo-(Arg-Gly-Asp-D-Phe-Orn)

[0304] Cyclo-(Arg-Gly-Asp-D-Trp-D-Orn)

[0305] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Orn)

[0306] Cyclo-(Arg-Gly-Asp-D-Phe-D-Orn)

[0307] Cyclo-(Arg-Gly-Asp-D-Trp-Dab)

[0308] Cyclo-(Arg-Gly-Asp-D-Tyr-Dab)

[0309] Cyclo-(Arg-Gly-Asp-D-Trp-Dap)

[0310] Cyclo-(Arg-Gly-Asp-D-Tyr-Dap)

[0311] Cyclo-(Arg-Gly-Asp-D-Phe-Dap)

[0312] Cyclo-(Arg-Gly-Asp-D-Trp-D-Dap)

[0313] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Dap)

[0314] Cyclo-(Arg-Gly-Asp-D-Phe-D-Dap)

[0315] gives the following peptides:

[0316] Cyclo-(Arg-Gly-Asp-D-Trp-Lys(N^(ε)-BOC-Aha))

[0317] Cyclo-(Arg-Gly-Asp-D-Tyr-Lys(N^(ε)-BOC-Aha))

[0318] Cyclo-(Arg-Gly-Asp-D-Phe-D-Lys(N^(ε)-BOC-Aha))

[0319] Cyclo-(Arg-Gly-As p-D-Phe-Cys(S-BOC-Aha))

[0320] Cyclo-(Arg-Gly-Asp-D-Phe-Dab(N^(γ)-BOC-Aha))

[0321] Cyclo-(Arg-Gly-Asp-D-Trp-D-Cys(S-BOC-Aha))

[0322] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Cys(S-BOC-Aha))

[0323] Cyclo-(Arg-Gly-Asp-Phe-D-Lys(N^(ε)-BOC-Aha))

[0324] Cyclo-(Arg-Gly-Asp-Trp-D-Lys(N^(ε)-BOC-Aha))

[0325] Cyclo-(Arg-Gly-Asp-Tyr-D-Lys(N^(ε)-BOC-Aha))

[0326] Cyclo-(Arg-Gly-Asp-Phe-D-Cys(S-BOC-Aha))

[0327] Cyclo-(Arg-Gly-Asp-Phe-Dab(N^(γ)-BOC-Aha))

[0328] Cyclo-(Arg-Gly-Asp-Trp-D-Cys(S-BOC-Aha))

[0329] Cyclo-(Arg-Gly-Asp-Tyr-D-Cys(S-BOC-Aha))

[0330] Cyclo-(Arg-Gly-Asp-D-Trp-Orn(N^(δ)-BOC-Aha))

[0331] Cyclo-(Arg-Gly-Asp-D-Tyr-Orn(N^(δ)-BOC-Aha))

[0332] Cyclo-(Arg-Gly-Asp-D-Phe-Orn(N^(δ)-BOC-Aha))

[0333] Cyclo-(Arg-Gly-Asp-D-Trp-D-Orn(N^(δ)-BOC-Aha))

[0334] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Orn(N^(δ)-BOC-Aha))

[0335] Cyclo-(Arg-Gly-Asp-D-Phe-D-Orn(N^(δ)-BOC-Aha))

[0336] Cyclo-(Arg-Gly-Asp-D-Trp-Dab(N^(γ)-BOC-Aha))

[0337] Cyclo-(Arg-Gly-Asp-D-Tyr-Dab(N^(γ)-BOC-Aha))

[0338] Cyclo-(Arg-Gly-Asp-D-Trp-Dap(N^(β)-BOC-Aha))

[0339] Cyclo-(Arg-Gly-Asp-D-Tyr-Dap(N^(β)-BOC-Aha))

[0340] Cyclo-(Arg-Gly-Asp-D-Tyr-Dap(N^(β)-BOC-Aha))

[0341] Cyclo-(Arg-Gly-Asp-D-Trp-D-Dap(N^(β)-BOC-Aha))

[0342] Cyclo-(Arg-Gly-Asp-D-Phe-D-Dap(N^(β)-BOC-Aha))

[0343] Cyclo-(Arg-Gly-Asp-D-Phe-D-Dap(N^(β)-BOC-Aha)).

[0344] After eliminating the BOC group in HCl/dioxane, the followingcompounds (“A”) are obtained:

[0345] Cyclo-(Arg-Gly-Asp-D-Trp-Lys(N^(ε)-Aha))

[0346] Cyclo-(Arg-Gly-Asp-D-Tyr-Lys(N^(ε)-Aha))

[0347] Cyclo-(Arg-Gly-Asp-D-Phe-D-Lys(N^(ε)-Aha))

[0348] Cyclo-(Arg-Gly-Asp-D-Phe-Cys(S-Aha))

[0349] Cyclo-(Arg-Gly-Asp-D-Phe-Dab(N^(γ)-Aha))

[0350] Cyclo-(Arg-Gly-Asp-D-Trp-D-Cys(S-Aha))

[0351] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Cys(S-Aha))

[0352] Cyclo-(Arg-Gly-Asp-Phe-D-Lys(N^(ε)-Aha))

[0353] Cyclo-(Arg-Gly-Asp-Trp-D-Lys(N^(ε)-Aha))

[0354] Cyclo-(Arg-Gly-Asp-Tyr-D-Lys(N^(ε)-Aha))

[0355] Cyclo-(Arg-Gly-Asp-Phe-D-Cys(S-Aha))

[0356] Cyclo-(Arg-Gly-Asp-Phe-Dab(N^(γ)-Aha))

[0357] Cyclo-(Arg-Gly-Asp-Trp-D-Cys(S-Aha))

[0358] Cyclo-(Arg-Gly-Asp-Tyr-D-Cys(S-Aha))

[0359] Cyclo-(Arg-Gly-Asp-D-Trp-Orn(N^(δ)-Aha))

[0360] Cyclo-(Arg-Gly-Asp-D-Tyr-Orn(N^(δ)-Aha))

[0361] Cyclo-(Arg-Gly-Asp-D-Phe-Orn(N^(δ)-Aha))

[0362] Cyclo-(Arg-Gly-Asp-D-Trp-D-Orn(N⁶⁷ -Aha))

[0363] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Orn(N^(δ)-Aha))

[0364] Cyclo-(Arg-Gly-Asp-D-Phe-D-Orn(N^(δ)-Aha))

[0365] Cyclo-(Arg-Gly-Asp-D-Trp-Dab(N^(γ)-Aha))

[0366] Cyclo-(Arg-Gly-Asp-D-Tyr-Dab(N^(γ)-Aha))

[0367] Cyclo-(Arg-Gly-Asp-D-Trp-Dap(N^(β)-Aha))

[0368] Cyclo-(Arg-Gly-Asp-D-Tyr-Dap(N^(β)-Aha))

[0369] Cyclo-(Arg-Gly-Asp-D-Phe-Dap(N^(β)-Aha))

[0370] Cyclo-(Arg-Gly-Asp-D-Trp-D-Dap(N^(β)-Aha))

[0371] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Dap(N^(β)-Aha))

[0372] Cyclo-(Arg-Gly-Asp-D-Phe-D-Dap(N^(β)-Aha)).

[0373] The following are obtained by reaction with octanoyl anhydride:

[0374] Cyclo-(Arg-Gly-Asp-D-Trp-Lys(N^(ε)-Oct-Aha))

[0375] Cyclo-(Arg-Gly-Asp-D-Tyr-Lys(N^(ε)-Oct-Aha))

[0376] Cyclo-(Arg-Gly-Asp-D-Phe-D-Lys(N^(ε)-Oct-Aha))

[0377] Cyclo-(Arg-Gly-Asp-D-Phe-Cys(S-Oct-Aha))

[0378] Cyclo-(Arg-Gly-Asp-D-Phe-Dab(N^(γ)-Oct-Aha))

[0379] Cyclo-(Arg-Gly-Asp-D-Trp-D-Cys(S-Oct-Aha))

[0380] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Cys(S-Oct-Aha))

[0381] Cyclo-(Arg-Gly-Asp-Phe-D-Lys(N^(ε)-Oct-Aha))

[0382] Cyclo-(Arg-Gly-Asp-Trp-D-Lys(N^(ε)-Oct-Aha))

[0383] Cyclo-(Arg-Gly-Asp-Tyr-D-Lys(N^(ε)-Oct-Aha))

[0384] Cyclo-(Arg-Gly-Asp-Phe-D-Cys(S-Oct-Aha))

[0385] Cyclo-(Arg-Gly-Asp-Phe-Dab(N^(γ)-Oct-Aha))

[0386] Cyclo-(Arg-Gly-Asp-Trp-D-Cys(S-Oct-Aha))

[0387] Cyclo-(Arg-Gly-Asp-Tyr-D-Cys(S-Oct-Aha))

[0388] Cyclo-(Arg-Gly-Asp-D-Trp-Orn(N^(δ)-Oct-Aha))

[0389] Cyclo-(Arg-Gly-Asp-D-Tyr-Orn(N^(δ)-Oct-Aha))

[0390] Cyclo-(Arg-Gly-Asp-D-Phe-Orn(N^(δ)-Oct-Aha))

[0391] Cyclo-(Arg-Gly-Asp-D-Trp-D-Orn(N^(δ)-Oct-Aha))

[0392] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Orn(N^(δ)-Oct-Aha))

[0393] Cyclo-(Arg-Gly-Asp-D-Phe-D-Orn(N^(δ)-Oct-Aha))

[0394] Cyclo-(Arg-Gly-Asp-D-Trp-Dab(N^(γ)-Oct-Aha))

[0395] Cyclo-(Arg-Gly-Asp-D-Tyr-Dab(N^(γ)-Oct-Aha))

[0396] Cyclo-(Arg-Gly-Asp-D-Trp-Dap(N^(β)-Oct-Aha))

[0397] Cyclo-(Arg-Gly-Asp-D-Tyr-Dap(N^(β)-Oct-Aha))

[0398] Cyclo-(Arg-Gly-Asp-D-Phe-Dap(N^(β)-Oct-Aha))

[0399] Cyclo-(Arg-Gly-Asp-D-Trp-D-Dap(N^(β)-Oct-Aha))

[0400] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Dap(N^(β)-Oct-Aha))

[0401] Cyclo-(Arg-Gly-Asp-D-Phe-D-Dap(N^(β)-Oct-Aha)).

[0402] The following are obtained by analogous reaction of the “A”compounds with FCA-N-succinimidyl ester:

[0403] Cyclo-(Arg-Gly-Asp-D-Trp-Lys(N^(ε)-FCA-Aha))

[0404] Cyclo-(Arg-Gly-Asp-D-Tyr-Lys(N^(ε)-FCA-Aha))

[0405] Cyclo-(Arg-Gly-Asp-D-Phe-D-Lys(N^(ε)-FCA-Aha))

[0406] Cyclo-(Arg-Gly-Asp-D-Phe-Cys(S-FCA-Aha))

[0407] Cyclo-(Arg-Gly-Asp-D-Phe-Dab(N^(γ)-FCA-Aha))

[0408] Cyclo-(Arg-Gly-Asp-D-Trp-D-Cys(S-FCA-Aha))

[0409] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Cys(S-FCA-Aha))

[0410] Cyclo-(Arg-Gly-Asp-Phe-D-Lys(N^(ε)-FCA-Aha))

[0411] Cyclo-(Arg-Gly-Asp-Trp-D-Lys(N^(ε)-FCA-Aha))

[0412] Cyclo-(Arg-Gly-Asp-Tyr-D-Lys(N^(ε)-FCA-Aha))

[0413] Cyclo-(Arg-Gly-Asp-Phe-D-Cys(S-FCA-Aha))

[0414] Cyclo-(Arg-Gly-Asp-Phe-Dab(N^(γ)-FCA-Aha))

[0415] Cyclo-(Arg-Gly-Asp-Trp-D-Cys(S-FCA-Aha))

[0416] Cyclo-(Arg-Gly-Asp-Tyr-D-Cys(S-FCA-Aha))

[0417] Cyclo-(Arg-Gly-Asp-D-Trp-Orn(N^(δ)-FCA-Aha))

[0418] Cyclo-(Arg-Gly-Asp-D-Tyr-Orn(N^(δ)-FCA-Aha))

[0419] Cyclo-(Arg-Gly-Asp-D-Phe-Orn(N^(δ)-FCA-Aha))

[0420] Cyclo-(Arg-Gly-Asp-D-Trp-D-Orn(N^(δ)-FCA-Aha))

[0421] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Orn(N^(δ)-FCA-Aha))

[0422] Cyclo-(Arg-Gly-Asp-D-Phe-D-Orn(N^(δ)-FCA-Aha))

[0423] Cyclo-(Arg-Gly-Asp-D-Trp-Dab(N^(γ)-FCA-Aha))

[0424] Cyclo-(Arg-Gly-Asp-D-Tyr-Dab(N^(γ)-FCA-Aha))

[0425] Cyclo-(Arg-Gly-Asp-D-Trp-Dap(N^(β)-FCA-Aha))

[0426] Cyclo-(Arg-Gly-Asp-D-Tyr-Dap(N^(β)-FCA-Aha))

[0427] Cyclo-(Arg-Gly-Asp-D-Phe-Dap(N^(β)-FCA-Aha))

[0428] Cyclo-(Arg-Gly-Asp-D-Trp-D-Dap(N^(β)-FCA-Aha))

[0429] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Dap(N^(β)-FCA-Aha))

[0430] Cyclo-(Arg-Gly-Asp-D-Phe-D-Dap(N^(β)-FCA-Aha)).

[0431] The following are obtained by analogous reaction of “A” compoundswith O-acetylsalicylic acid N-succinimidyl ester:

[0432] Cyclo-(Arg-Gly-Asp-D-Trp-Lys(N^(ε)-Ac-Sal-Aha))

[0433] Cyclo-(Arg-Gly-Asp-D-Tyr-Lys(N^(ε)-Ac-Sal-Aha))

[0434] Cyclo-(Arg-Gly-Asp-D-Phe-D-Lys(N^(ε)-Ac-Sal-Aha))

[0435] Cyclo-(Arg-Gly-Asp-D-Phe-Cys(S-Ac-Sal--Aha))

[0436] Cyclo-(Arg-Gly-Asp-D-Phe-Dab(N^(γ)-Ac-Sal-Aha))

[0437] Cyclo-(Arg-Gly-Asp-D-Trp-D-Cys(S-Ac-Sal-Aha))

[0438] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Cys(S-Ac-Sal-Aha))

[0439] Cyclo-(Arg-Gly-Asp-Phe-D-Lys(N^(ε)-Ac-Sal-Aha))

[0440] Cyclo-(Arg-Gly-Asp-Trp-D-Lys(N^(ε)-Ac-Sal-Aha))

[0441] Cyclo-(Arg-Gly-Asp-Tyr-D-Lys(N^(ε)-Ac-Sal-Aha))

[0442] Cyclo-(Arg-Gly-Asp-Phe-D-Cys(S-Ac-Sal-Aha))

[0443] Cyclo-(Arg-Gly-Asp-Phe-Dab(N^(γ)-Ac-Sal-Aha))

[0444] Cyclo-(Arg-Gly-Asp-Trp-D-Cys(S-Ac-Sal-Aha))

[0445] Cyclo-(Arg-Gly-Asp-Tyr-D-Cys(S-Ac-Sal-Aha))

[0446] Cyclo-(Arg-Gly-Asp-D-Trp-Orn(N^(δ)-Ac-Sal-Aha))

[0447] Cyclo-(Arg-Gly-Asp-D-Tyr-Orn(N^(δ)-Ac-Sal-Aha))

[0448] Cyclo-(Arg-Gly-Asp-D-Phe-Orn(N^(δ)-Ac-Sal-Aha))

[0449] Cyclo-(Arg-Gly-Asp-D-Trp-D-Orn(N^(δ)-Ac-Sal-Aha))

[0450] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Orn(N^(δ)-Ac-Sal-Aha))

[0451] Cyclo-(Arg-Gly-Asp-D-Phe-D-Orn(N^(δ)-Ac-Sal-Aha))

[0452] Cyclo-(Arg-Gly-Asp-D-Trp-Dab(N^(γ)-Ac-Sal-Aha))

[0453] Cyclo-(Arg-Gly-Asp-D-Tyr-Dab(N^(γ)-Ac-Sal-Aha))

[0454] Cyclo-(Arg-Gly-Asp-D-Trp-Dap(N^(β)-Ac-Sal-Aha))

[0455] Cyclo-(Arg-Gly-Asp-D-Tyr-Dap(N^(β)-Ac-Sal-Aha))

[0456] Cyclo-(Arg-Gly-Asp-D-Phe-Dap(N^(β)-Ac-Sal-Aha))

[0457] Cyclo-(Arg-Gly-Asp-D-Trp-D-Dap(N^(β)-Ac-Sal-Aha))

[0458] Cyclo-(Arg-Gly-Asp-D-Tyr-D-Dap(N^(β)-Ac-Sal-Aha))

[0459] Cyclo-(Arg-Gly-Asp-D-Phe-D-Dap(N^(β)-Ac-Sal-Aha)),

[0460] with the deacetylated compounds, which are separated off undercustomary chromatographic conditions, also resulting at the same time.

EXAMPLE 5

[0461] Cyclo-(Arg-Gly-Asp-D-Phe-Lys (N^(ε)-HSEtCO))×TFA; RT [B] 18.54;FAB 692 is obtained, after the customary working-up, by eliminating thetrityl group from cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-TrtSEtCO)) usingTFA/thiophenol.

EXAMPLE 6

[0462] 2.0 g of succinic acid N-succinimidyl ester monomethyl ester and0.5 g of triethylamine are added to a solution of 3.05 g ofcyclo-(Arg-Gly-Asp-D-Phe-Lys) in 100 ml of dichloromethane. The mixtureis stirred at room temperature for 5 hours, andcyclo-(Arg-Gly-Asp-D-Phe-Lys (N^(ε)-H₃COCO (CH₂)₂CO)) is obtained afterthe customary working-up.Cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-HOCO(CH₂)₂CO)) is obtained byhydrolysing the ester with aqueous potassium hydroxide.Cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-SuN-O—CO (CH₂)₂CO)) is obtained bysubsequent reaction with HONSu in ethyl acetate. The following compoundis obtained, in analogy with Example 1, by reaction withcyclo-(Arg-Gly-Asp-D-Phe-Lys-Gly): cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)—CO(CH₂)₂CO—R²)), in which R² is cyclo-(Arg-Gly-Asp-D-Phe-Lys(N^(ε)-)-Gly)

EXAMPLE 7

[0463] 0.5 ml of acetic acid and 0.5 g of palladium on active carbon areadded to a solution of 1.17 g ofcyclo-(Arg(Mtr)-Gly-Asp(OBut)-D-Phe-Lys(CBZ)) in 50 ml ofdimethylacetamide, and the mixture is stirred for 2 hours under ahydrogen atmosphere. Cyclo-(Arg(Mtr)Gly-Asp(OBut)-D-Phe-Lys) (“B”); RT[A, 30-80% acetonitrile] 18.6 is obtained after separating off thecatalyst and after the customary working-up.

[0464] 0.075 g of succinic anhydride are added to a solution of 0.3 g of“B” in 15 ml of DMF and the mixture is stirred at room temperature for12 hours. 0.26 g of cyclo-(Arg(Mtr)-Gly-Asp(OBut)-D-Phe-Lys(N^(ε)—CO—(CH₂)₂—COOH)) (“C”); RT [A, 30-80% acetonitrile] 19.2; FAB 972is obtained after the customary working-up.

[0465] 0.1 g of EDCl×HCl, 0.075 g of HOBt and a solution of 0.3 g of “B”in 15 ml of DMF are added to a solution of 0.23 g of “B” in 20 ml ofDMF, and the mixture is stirred for 12 hours.Cyclo-(Arg(Mtr)-Gly-Asp(OBut)-D-Phe-Lys)₂(COCH₂CH₂CO) (“D”); RT [A,30-80% acetonitrile] 26.6; FAB 1826 is obtained after the customaryworking-up.

[0466] A solution consisting of 85.5% TFA, 2% water, 2.5% ethanedithiol,5% phenol, 5% thioanisole and 0.25 g of “D” is stirred at roomtemperature for 24 hours. Cyclo-(Arg-Gly-Asp-D-Phe-Lys)₂ (COCH₂CH₂CO);RT [A, 10-50% acetonitrile] 20.2; FAB 1289 is obtained after thecustomary working-up.

[0467] The following compound is obtained in an analogous manner fromcyclo-(Arg(Mtr)-Gly-Asp(OBut)-D-Phe-Lys(CBZ)) by reacting the latterwith dithiodipropionic acid (DTDP-OH) under the same conditions aspreviously:

[0468] Bis-N^(ε)-cyclo-(Arg-Gly-Asp-D-Phe-Lys)-DTDP; RT 20.73; FAB 1382.

[0469] The following examples relate to pharmaceutical preparations:

EXAMPLE A Injection Vials

[0470] A solution of 100 g of an active compound of the formula I and 5g of disodium hydrogen phosphate is adjusted, in 3 l of double distilledwater, to pH 6.5 with 2 n hydrochloric acid, sterilized by filtrationand used to fill injection vials; the solution is lyophilized, and thevials sealed, under sterile conditions. Each injection vial contains 5mg of active compound.

EXAMPLE B Suppositories

[0471] A mixture of 20 g of an active compound of the formula I with 100g of soya bean lecithin and 1400 g of cocoa butter is melted, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive compound.

EXAMPLE C Solution

[0472] A solution is prepared from 1 g of an active compound of theformula I, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄. 12 H₂O and 0.1 gof benzalkonium chloride in 940 ml of double distilled water. Thesolution is adjusted to pH 6.8, made up to 1 l and sterilized byirradiation. This solution can be used in the form of eyedrops.

EXAMPLE D Ointment

[0473] 500 mg of an active compound of the formula I is mixed with 99.5g of vaseline under asceptic conditions.

EXAMPLE E Tablets

[0474] A mixture of 1 kg of active compound of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is compressed into tablets in a customary manner, such thateach tablet contains 10 mg of active compound.

EXAMPLE F Coated Tablets

[0475] Tablets are compressed in analogy with Example E, with thetablets then being coated, in a customary manner, with a coatingcomposed of sucrose, potato starch, talc, tragacanth and dye.

EXAMPLE G Capsules

[0476] Hard gelatine capsules are filled, in a customary manner, with 2kg of active compound of the formula I such that each capsule contains20 mg of the active compound.

EXAMPLE H Ampoules

[0477] A solution of 1 kg of active compound of the formula I in 60 l ofdouble distilled water is sterilized by filtration and used to fillampoules; the solution is lyophilized, and the ampoules are sealed,under sterile conditions. Each ampoule contains 10 mg of activecompound.

EXAMPLE I Inhalation Spray

[0478] 14 g of active compound of the formula I are dissolved in 10 l ofisotonic NaCl solution and the solution is used to fill commerciallyavailable spraying vessels which have a pumping mechanism. The solutioncan be sprayed into the mouth or nose. One spray burst (approximately0.1 ml) corresponds to a dose of about 0.14 mg.

1. Compounds of the formula I R¹—Q¹—X—Q²—R²   I in which Q¹, Q² are, ineach case independently of each other, either absent or—NH—(CH₂)_(n)—CO—, R¹, R² are, in each case independently of each other,either absent or cyclo-(Arg-Gly-Asp-Z), where Z is bonded in the sidechain to Q¹ or Q² or, if Q¹ and/or Q² is/are absent, to X, and where atleast one of the radicals R¹ or R² must always be present, X is—CO—R¹⁸—CO—, and if R¹—Q¹— or R²—Q²— is absent, R¹⁰, R¹³, R¹⁶, Het—CO ora fluorescent dye residue which is linked by way of a —CONH—, —COO—,—NH—C(═S)—NH—, —NH—C—(═O)—NH—, —SO₂NH— or —NHCO— bond, Z is, in eachcase independently of each other, an amino acid residue or a di-, tri-or tetra-peptide residue, where the amino acids are selected,independently of each other, from a group consisting of Ala, Asn, Asp,Arg, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr,Trp, Tyr, Val or M, where the said amino acids can also be derivatizedand the amino acid residues are linked to each other, in peptide manner,by way of the α-amino and α-carboxyl groups, and where M is alwayspresent, M is NH(R⁸)—CH(R³)—COOH, R³ is —R⁵—R⁴, —R⁶—R⁴ or —R⁷—R⁴, R⁴ isOH, NH₂, SH or COOH, R⁵ is alkylene having 1-6 carbon atoms, R⁶ isalkylenephenylene having 7-14 carbon atoms, R⁷ is alkylenephenylalkylenehaving 8-15 carbon atoms, R⁸ is H, A or alkylenephenyl having 7-12carbon atoms, A is alkyl having 1-6 carbon atoms, R¹⁰ is alkanoyl having1-18 carbon atoms which is unsubstituted or substituted once by COOH,COOA, SR¹¹ or NR¹²R^(12′), R¹¹ is H or trityl, pyridyl-2-thio oralkylthio having 1-6 carbon atoms, R¹², R^(12′) are, in each caseindependently of each other, H, alkyl having 1-8 carbon atoms or anamino-protecting group, R¹³ is aroyl having 7-11 carbon atoms which isunsubstituted or substituted once or twice by alkyl having 1-6 carbonatoms, alkoxy having 1-4 carbon atoms, alkanoyl having 1-8 carbon atoms,Hal, SR¹⁴ or NR¹⁵R^(15′), R¹⁴ is H or A, R¹⁵, R^(15′) are, in each caseindependently of each other, H or A, R¹⁶ is aralkanoyl having 7-19carbon atoms which is unsubstituted or substituted once, twice or threetimes in the aryl moiety by Hal, alkoxy having 1-6 carbon atoms or OHand in which the aryl moiety can also be a

 group, E is CH₂ or O, D is carbonyl or [C(R¹⁷R^(17′))]_(m), R¹⁷,R^(17′) are, in each case independently of each other, H or A, R¹⁸ isabsent, or is R¹⁹, R²⁰, R¹⁹—R²⁰—R¹⁹, or phenylene which is unsubstitutedor substituted once or twice by R⁵, where the chain length of R⁵ is ineach case independent of each other, R¹⁹ is alkylene having 1-8 carbonatoms, where 1 or 2 methylene groups can be replaced by S, —CH═CH— or—C≡C—, R²⁰ is cycloalkylene having 3-7 carbon atoms, Hal is F, Cl, Br orI, Het is a mononuclear or binuclear saturated, unsaturated or aromaticheterocycle having from 1 to 4 N, O and/or S atoms, bonded via N or C,which can be unsubstituted or substituted once, twice or three times byHal, A, R³, NR⁴R^(4′), CN, NO₂ and/or carbonyl oxygen, n is 1, 2, 3, 4,5, 6, 7, 8, 9 or 10, and m is 1 or 2, where, provided that the residuesare residues of optically active amino acids and amino acid derivatives,both the D and the L forms are included, and the salts thereof. 2.Compounds of the formula I according to claim 1 R¹—Q¹—X—Q²—R²   I a) inwhich Q¹, Q² and R² are absent, R¹ is cyclo-(Arg-Gly-Asp-D-Phe-Lys), andX is acetyl; b) in which Q¹, Q² and R² are absent, R¹ iscyclo-(Arg-Gly-Asp-D-Phe-Lys), and X is —CO—(CH₂)₂—SH; c) in which Q¹,Q² and R² are absent, R¹ is cyclo-(Arg-Gly-Asp-D-Phe-Lys), and X issalicyloyl; d) in which Q¹ and Q² are absent, R¹ and R² arecyclo-(Arg-Gly-Asp-D-Phe-Lys), and X is —CO—(CH₂)₂—CO—; e) in which Q²and R² are absent, Q¹ is —NH—(CH₂)₅—CO—, R¹ iscyclo-(Arg-Gly-Asp-D-Phe-Lys), and X is acetyl; f) in which Q² and R²are absent, Q¹ is —NH—(CH₂)₅—CO—, R¹ is cyclo-(Arg-Gly-Asp-D-Phe-Lys),and X is fluoresceinoyl; g) in which Q² and R² are absent, Q¹ is—NH—(CH₂)₅—CO—, R¹ is cyclo-(Arg-Gly-Asp-D-Phe-Lys), and X istert-butyloxycarbonyl; and the physiologically harmless salts of thesaid compounds.
 3. Process for preparing compounds of the formula Iaccording to claim 1, and their salts, characterized in that a) acompound of the formula II H—Q¹—R¹   II  in which Q¹ and R¹ have themeaning given in claim 1, is reacted, in an acylation reaction, with acompound of the formula III X—L   III  in which X has the meaning givenin claim 1, and L is Cl, Br, I or a free or reactive functionallymodified OH group, or b) in that a compound of the formula IV H—Q²—R²  IV  in which Q² and R² have the meaning given in claim 1, is reacted,in an acylation reaction, with a compound of the formula V R¹—Q¹—X—L   V in which R¹, Q¹, X and L have the given meaning, or c) in that acompound of the formula II H—Q¹—R   II  in which Q¹ and R¹ have themeaning given in claim 1, is reacted, in an addition reaction, with acompound of the formula VI X—U   VI  in which X has the meaning given inclaim 1, and U is —N═C═O, —N═C═S or maleimidyl, or d) in that they areliberated from one of their functional derivatives by treatment with asolvolysing or hydrogenolysing agent, and/or in that a basic or acidiccompound of the formula I is converted into one of its salts bytreatment with an acid or base.
 4. Process for producing pharmaceuticalpreparations, characterized in that a compound of the formula Iaccording to claim 1, and/or one of its physiologically harmless salts,is brought into a suitable dosage form together with at least one solid,liquid or semisolid carrier substance or auxiliary substance. 5.Pharmaceutical preparation, characterized by a content of at least onecompound of the formula I according to claim 1 and/or one of itsphysiologically harmless salts.
 6. Compounds of the formula I accordingto claim 1, and their physiologically harmless salts, as integrininhibitors for controlling pathologically angiogenic diseases,thrombosis, cardiac infarct, coronary heart diseases, arteriosclerosis,tumours, osteoporosis, inflammations and infections.
 7. Use of compoundsof the formula I according to claim 1, and/or their physiologicallyharmless salts, for producing a pharmaceutical.
 8. Use of compounds offormula I according to claim 1, and/or their physiologically harmlesssalts, in the control of diseases.
 9. Use of compounds of the formula Iaccording to claim 1, where X is a fluorescent dye residue which islinked by way of a —CONH—, —COO—, —NH—C(═S)—NH—, —NH—C—(═O)—NH—, —SO₂NH—or —NHCO— bond, as diagnostic markers in FACS analysis and fluorescencemicroscopy.
 10. Use of compounds of the formula I according to claim 1in affinity chromatography.